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Experimental activation of the innate immune system has contributed significantly to both our understanding of how psychological factors influence immune function as well as how immune activity influences the brain and behavior. The annual influenza vaccine can be used to interrogate the effects of mild immune stimulation on day-to-day changes in psychological processes in human subjects that range across the lifespan and in both clinical and non-clinical populations. Yet, the immune response to the influenza vaccine in the days immediately following its administration are not well characterized. The present study describes changes in inflammatory and antiviral gene expression within circulating immune cells, plasma cytokines, and C-reactive protein (CRP) following receipt of the flu vaccine, and further reports the association between several common behavioral health factors and the acute immune response. Participants were 65 adults (mean age 18.81 ± 1.03 years; 66.2% female) who provided a blood sample immediately before and then 24 h after receiving the vaccine. A subsample also provided additional blood samples at 48 and 72 h. Plasma was assayed for CRP, IL-6, IL-10, IL-8, TNF-α, and IFN-γ, and peripheral blood mononuclear cell RNA was sequenced for evidence of change in expression of an a priori set of type 1 interferon (IFN) and inflammatory response genes (INFLAM). Plasma cytokines, CRP, and IFN response genes increased 24 h after vaccination, all ps < .001. The increase in IFN gene expression correlated with the observed increase in plasma cytokines and CRP, p < .0001. The immune response to influenza vaccination at 24-hours was moderated by anxiety symptoms, BMI, being female, sleep, and history of influenza vaccination. These factors and their associations with common immune challenges may be useful in studies interrogating the origins of immune dysregulation. The annual influenza vaccine is an accessible and reliable exogenous activator of both circulating and transcriptional markers of innate immune reactivity, with sensitivity to behavioral health factors relevant for psychoneuroimmunology research., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Social connections are crucial to human health and well-being. Previous research on molecular mechanisms in health has focused primarily on the individual-level perception of social connections (e.g., loneliness). This study adopted socio-centric social network analysis that includes all social ties from the entire population of interest to examine the group-level social connections and their association with a molecular genomic measure of health., Methods: Using socio-centric (global) social network data from an entire village in Korea, we investigated how social network characteristics are related to immune cell gene expression among older adults. Blood samples were collected (N = 53, 65-79 years) and mixed effect linear model analyses were performed to examine the association between social network characteristics and Conserved Transcriptional Response to Adversity (CTRA) RNA expression patterns., Results: Social network positions measured by k-core score, the degree of cohesive core positions in an entire village, were significantly associated with CTRA downregulation. Such associations emerged above and beyond the effects of perceived social isolation (loneliness) and biobehavioral risk factors (smoking, alcohol, BMI, etc.). Social network size, defined as degree centrality, was also associated with reduced CTRA gene expression, but its association mimicked that of perceived social isolation (loneliness)., Conclusions: The current findings implicate community-level social network characteristics in the regulation of individual human genome function above and beyond individual-level perceptions of connectedness., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Alterations in immune system gene expression have been implicated in psychopathology, but it remains unclear whether similar associations occur for intraindividual variations in emotion. The present study examined whether positive emotion and negative emotion were related to expression of pro-inflammatory and antiviral genes in circulating leukocytes from a community sample of 90 adolescents (M age = 16.3 years, SD = 0.7; 51.1% female). Adolescents reported their positive emotion and negative emotion and provided blood samples twice, five weeks apart. Using a multilevel analytic framework, we found that within-individual increases in positive emotion were associated with reduced expression of both pro-inflammatory and Type I interferon (IFN) response genes, even after adjusting for demographic and biological covariates, and for leukocyte subset abundance. By contrast, increases in negative emotion were related to higher expression of pro-inflammatory and Type I IFN genes. When tested in the same model, only associations with positive emotion emerged as significant, and increases in overall emotional valence were associated with both lower pro-inflammatory and antiviral gene expression. These results are distinct from the previously observed Conserved Transcriptional Response to Adversity (CTRA) gene regulation pattern characterized by reciprocal changes in pro-inflammatory and antiviral gene expression and may reflect alterations in generalized immunologic activation. These findings highlight one biological pathway by which emotion may potentially impact health and physiological function in the context of the immune system, and future studies can investigate whether fostering positive emotion may promote adolescent health through changes in the immune system., Competing Interests: Declarations of interest None., (Copyright © 2023. Published by Elsevier Ltd.)

Marital quality shares ties to inflammation-related conditions like cardiovascular disease and diabetes. Lab-based studies implicate hostility during marital conflict as a mechanism via inflammatory reactivity, but little attention has been paid to the inflammatory aftermath of other marital exchanges. A spouse's emotional distress is an important but overlooked context for middle-aged and older couples, as conflict declines and networks shrink. To examine the links of spousal distress to changes in proinflammatory gene expression, 38 adults ages 40-81 witnessed their spouse relive an upsetting personal memory aloud, rated their mood before and after, and provided blood samples at baseline and twice post-task; they also shared their own upsetting memory and discussed a marital problem in the interim. Those whose spouse disclosed their upsetting memory with greater emotional intensity showed larger elevations in proinflammatory gene expression 30-40 min and 80-90 min after the task. The association replicated for listeners whose negative mood increased more in response to spousal disclosure. Findings were robust to behavior in the other emotional tasks, race, gender, age, alcohol, smoking, comorbidities, and sagittal abdominal diameter. These novel results identify spousal distress as a key marital context that may escalate inflammation-related health risks., Competing Interests: Conflicts of Interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Volunteering is associated with improved health and well-being outcomes, including a reduced risk of mortality. However, the biological mechanisms underlying the association between volunteering and healthy aging and longevity have not been well-established. We evaluated if volunteering was associated with reduced epigenetic age acceleration in older adults., Methods: We evaluated associations between volunteering and age acceleration, measured by 13 DNA methylation (DNAm) "epigenetic clocks" in 4011 older adults (M age =69 years; SD age =10 years) who participated in the Health and Retirement Study. We assessed 9 first-generation clocks (Horvath, Hannum, Horvath Skin, Lin, Garagnani, Vidalbralo, Weidner, Yang, and Bocklandt, which predict chronological age) and 4 second-generation clocks (Zhang, PhenoAge, GrimAge, and DunedinPoAm, which predict future disease or longevity). We quantified the total associations between volunteering and DNAm age acceleration as well as the extent to which these associations might be attributable to potential confounding by individual demographics (e.g., race), social demographics (e.g., income), health factors (e.g., diabetes), and health behaviors (e.g., smoking)., Results: Volunteering was associated with reduced epigenetic age acceleration across 6 epigenetic clocks optimized for predicting health and longevity (False Discovery Rate [FDR] q < 0.0001 for epigenetic clocks: PhenoAge, GrimAge, DunedinPoAm, Zhang mortality, Yang mitotic; FDR q < 0.01: Hannum). These associations were mostly independent of demographic and health factors, but substantially attenuated after adjusting for health behaviors., Conclusion: Volunteering was associated with reduced epigenetic age acceleration in 6 of 13 (mostly second-generation) epigenetic clocks. Results provide preliminary evidence that volunteering might provide health benefits through slower biological aging and implicate health behaviors as one potential mechanism of such effects., Competing Interests: Conflict of Interest Victor J. Strecher is Founder and Chief Executive Officer of Kumanu, Inc., a digital health and well-being company. For all other authors, declarations of interest: none., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Social connection has been linked to reduced disease risk and enhanced antiviral immunity, but it is unclear whether online social connections have similar effects to those previously documented for in-person/offline social relationships, or whether online connections can substitute for in-person social relations when the latter are restricted. We examined this question in the context of the COVID-19 pandemic, focusing specifically on an immune system gene regulation profile known as the conserved transcriptional response to adversity (CTRA), which is characterized by up-regulation of proinflammatory genes and down-regulation of genes linked to innate antiviral responses and antibody production., Methods: We analyzed CTRA RNA profiles in blood samples from 142 healthy young adults (69% female, 87% white) during the "social distancing" period of the COVID-19 pandemic. Mixed effect linear models quantified the relation of CTRA gene expression to measures of in-person social connection (number of friends, social eudaimonia, loneliness) and online psychosocial connection (online loneliness, perceived social value in online leisure and educational contexts, and internet use) while controlling for demographic and health factors., Results: Multiple indicators of in-person and generalized social connection were associated with lower CTRA gene expression, whereas no measure of online social connection showed any significant association with CTRA gene expression., Conclusion: Experiences of in-person social connection are associated with reduced CTRA gene expression during a period of restricted social interaction. In contrast, online social relationships show no such association. Digitally mediated social relations do not appear to substantially offset the absence of in-person/offline social connection in the context of immune cell gene regulation., Competing Interests: Declaration of Competing Interest none., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The number of US adults identifying as lesbian, gay, bisexual, transgender, or a different sexual identity has doubled since 2008, and about 40 % of the sexual and gender minority population identify as people of color. Minority stress theory posits that sexual and gender minorities are at particular risk for stress via stigma and discrimination at the structural, interpersonal, and individual levels. This stress, in turn, elevates the risk of adverse health outcomes across several domains. However, there remains a conspicuously limited amount of research on the psychoneuroimmunology of stress among sexual and gender minorities. We developed the Biopsychosocial Minority Stress Framework which posits that sexual minority status leads to unique experiences of minority stress which results in adverse health behavioral factors, elevated psychological distress and sleep disturbance, and immune dysregulation. Moderators in the model include both individual differences and intersectional identities. There is a crucial need to understand the biological-psychological axis of stress among the increasingly visible sexual and gender minority population to increase their health, longevity, and quality of life., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Chronic stress threatens an individual's capacity to maintain psychological and physiological homeostasis, but the molecular processes underlying the biological embedding of these experiences are not well understood. This is particularly true for marginalized groups, presenting a fundamental challenge to decreasing racial, economic, and gender-based health disparities. Physical and social environments influence genome function, including the transcriptional activity of core stress responsive genes. We studied the relationship between social experiences that are associated with systemic inequality (e.g., racial segregation, poverty, and neighborhood violence) and blood cell (leukocytes) gene expression, focusing on the activation of transcription factors (TF) critical to stress response pathways. The study used data from 68 women collected from a convenience sample in 2013 from the Southside of Chicago. Comparing single, low-income Black mothers living in neighborhoods with high levels of violence (self-reported and assessed using administrative police records) to those with low levels of violence we found no significant differences in expression of 51 genes associated with the Conserved Transcriptional Response to Adversity (CTRA). Using TELiS analysis of promoter TF-binding motif prevalence we found that mothers who self-reported higher levels of neighborhood stress showed greater expression of genes regulated by the glucocorticoid receptor (GR). These findings may reflect increased cortisol output from the hypothalamic-pituitary-adrenal (HPA) axis, or increased GR transcriptional sensitivity. Transcript origin analyses identified monocytes and dendritic cells as the primary cellular sources of gene transcripts up-regulated in association with neighborhood stress. The prominence of GR-related transcripts and the absence of sympathetic nervous system-related CTRA transcripts suggest that a subjective perception of elevated chronic neighborhood stress may be associated with an HPA-related defeat-withdrawal phenotype rather than a fight-or-flight phenotype. The defeat-withdrawal phenotype has been previously observed in animal models of severe, overwhelming threat. These results demonstrate the importance of studying biological embedding in diverse environments and communities, specifically marginalized populations such as low-income Black women., (Published by Elsevier Ltd.)

Objective: Mindfulness meditation has been shown to reduce distress and increase well-being among individuals with chronic disease, including breast cancer survivors. However, the neural correlates of these changes and their links with inflammatory biology are not yet known. The present study examined whether a mindfulness meditation intervention was associated with changes in neural responses to threat and reward from pre- to post-intervention, and whether those neural changes were associated with changes in markers of inflammation in breast cancer survivors., Methods: This was a single-arm trial of a standardized, validated 6-week mindfulness meditation intervention. Participants were 20 women who had been diagnosed and treated for early-stage breast cancer. Participants provided peripheral blood samples and underwent a 90-minute neuroimaging scan before and after the intervention, with a focus on tasks known to elicit activity in threat- and reward-related neural regions., Results: There were significant changes in neural responses to the two tasks of interest from pre to post-intervention (ps < 0.042). Participants showed significant reductions in amygdala activity in response to threatening images and significant increases in ventral striatum activity to rewarding images from pre- to post-intervention. Although changes in amygdala activity were not correlated with inflammatory markers, increases in ventral striatum activity were correlated with decreases in circulating concentrations of the proinflammatory cytokine IL-6 and the inflammatory marker CRP., Conclusions: These results, while preliminary, suggest that while a mindfulness meditation intervention can alter neural responses to both threat and nonsocial reward-related stimuli, changes in neural reward activity may be more closely linked to changes in circulating levels of inflammation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

A previous study found that Extraversion and Conscientiousness were associated with increased and decreased expression of a pre-specified set of pro-inflammatory indicator genes. The present study aimed to replicate these findings in a sample of adults from the Refresher Cohort of the Study of Midlife in the United States (MIDUS). Analysis of gene expression composite scores and generalized linear models that took into account the heterogeneity and non-independence of RNA expression across different genes found no significant associations between the pro-inflammatory indicator gene set and the Big Five domains of personality. In addition, there was no significant association between a pre-specified antiviral indicator gene set and the Big Five domains. These findings suggest that relations between Big Five personality and expression of these two immune response indicator gene sets do not consistently appear across samples and may be context-dependent in ways that remain to be elucidated.

Background: Happiness has traditionally been thought to comprise two parts - pleasure (hedonia) and meaning (eudaimonia). Even though the two types of happiness are correlated, genomics studies have found distinct transcriptional correlates of hedonia and eudaimonia, particularly in the Conserved Transcriptional Response to Adversity (CTRA) marked by up-regulation of proinflammatory genes and down-regulation of interferon-related genes. Eudaimonia has been associated with reduced CTRA gene expression in several studies, whereas hedonia shows no consistent association with the CTRA. However, most of these social genomics studies have been conducted in Western cultures with Caucasian samples, so it is unclear if these findings extended to non-Western cultures with other ethnic groups. Moreover, it is unknown whether age might modify the association between CTRA gene expression and eudaimonia. To this end, we examined in a sample of Koreans the relationship between CTRA profiles and measures of hedonia and eudaimonia, as well as the role of age in modulating the strength of those relationships., Methods: Blood samples were collected from 152 healthy Korean adults (mean age = 44.64; 50 % female). Well-being was measured using the Mental Health Continuum short form (MHC-SF), Ryff Scales of Psychological Well-being (PWB), and subjective well-being (SWB) scales. RNA transcriptome profiles were obtained by RNA sequencing. Mixed effect linear model analyses examined the association between CTRA gene expression and measures of MHC-SF, SWB, PWB (total scores and six subscales) and additional analyses examined a possible moderating role of age., Results: CTRA gene expression was significantly downregulated in association with the MHC-SF eudaimonic scores as well as the PWB total scores. Among the six domains of PWB, autonomy showed the strongest inverse correlation with CTRA profiles. Moreover, the inverse association between CTRA and PWB was stronger for older participants., Conclusion: Eudaimonia is associated with reduced CTRA gene expression in a Korean population, with particularly marked relationships for autonomy. Findings also suggest that aging with meaning may bring biological advantage in later life., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Exposure to adverse social factors has been associated with an altered inflammatory profile, a risk factor for several acute and chronic diseases. Differential gene expression may be a biological mediator in the relationship. In this study, associations between a range of social factors and expression of inflammation-related genes were investigated., Methods: Social factor and gene expression data were collected from 1,264 individuals in the Multi-Ethnic Study of Atherosclerosis (MESA). Inflammation-related genes were identified from the Gene Ontology database. The associations between social factors and gene expression were first assessed using the Global Analysis of Covariance (Global ANCOVA) gene set enrichment test. When the global test was significant, linear regression and elastic net penalized regression were employed to identify the individual gene transcripts within each gene set associated with the social factor., Results: Loneliness (p = 0.003), chronic burden (p = 0.002), and major or lifetime discrimination (p = 0.045) were significantly associated with global expression of the chronic inflammatory gene set. Of the 20 transcripts that comprise this gene set, elastic net selected 12 transcripts for loneliness, 8 for chronic burden, and 3 for major or lifetime discrimination. Major or lifetime discrimination was also associated with the inflammatory response (p = 0.029), regulation of the inflammatory response (p = 0.041), and immune response (p = 0.025) gene sets in global analyses, and 53, 136, and 26 transcripts were selected via elastic net for these gene sets respectively. There were no significant associations in linear regression analyses after adjustment for multiple testing., Conclusions: This study highlights gene expression as a biological mechanism through which social factors may affect inflammation., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2020. Published by Elsevier Ltd.)

To clarify the biological mechanisms underlying the relationship between pro-social behavior and health, this pilot study examined the impact of a 9-month intergenerational helping intervention on conserved transcriptional response to adversity (CTRA) gene expression profiles, which are characterized by up-regulation of genes involved in inflammation and down-regulation of genes involved in antiviral defenses. The Generation Xchange program trains and places older (age 50+) volunteers in K-3 rd grade classrooms to aid students' academic development (reading and math) and address behavioral issues (e.g., inability to focus during class, behaviors that disrupt class). Volunteers were predominately women (89%) and African American (94%) from the neighborhoods around the schools. Repeated measures planned contrast analysis of 53 CTRA indicator transcripts in 50 blood samples collected from 18 individuals on 2-3 occasions revealed a significant reduction in CTRA gene expression from baseline to the average of 3- and 9-month follow-up. The magnitude of individual decrease in CTRA gene expression correlated with the magnitude of individual increase in eudaimonic well-being over time (net of changes in hedonic well-being). In addition to clarifying biological pathways through which pro-social behavior might impact health, these pilot data suggest that the GenX program may have favorable effects on immune cell gene regulation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Racial disparities in health outcomes between African Americans and European Americans have been well-documented, but not fully understood. Chronic inflammation contributes to several of the diseases showing racial disparities (e.g., Human Immunodeficiency Virus [HIV]), and racial differences in stress exposure (e.g., experiences of racial discrimination) that stimulate pro-inflammatory processes that may contribute to differential health outcomes. We performed a cross-sectional bioinformatic analyses relating perceived discrimination (as measured by the Perceived Ethnic Discrimination Questionnaire [PED-Q]) to the activity of pro-inflammatory, neuroendocrine, and antiviral transcription control pathways relevant to the conserved transcriptional response to adversity (CTRA) in peripheral blood leukocytes. Subjects were 71 individuals (37 HIV-seropositive (HIV+); 34 HIV-seronegative (HIV-)) (mean age = 53 years, range 27-63), who self-identified either as African American/Black (n = 48) or European American/White (n = 23). This provided the opportunity to examine the independent effects of race and HIV, as well as the modifying role of perceived discrimination on pathways involved in CTRA. Exploratory analysis examined the interactive effects of HIV and race on pathways involved in CTRA. Relative to European Americans, African Americans showed increased activity of two key pro-inflammatory transcription control pathways (NF- кB and AP-1) and two stress-responsive signaling pathways (CREB and glucocorticoid receptor); these effects did not differ significantly as a function of HIV infection (HIV x Race interaction, all p > .10). Results suggested that differences in experiences of racial discrimination could potentially account for more than 50% of the total race-related difference in pro-inflammatory transcription factor activity. In sum, differential exposure to racial discrimination may contribute to racial disparities in health outcomes in part by activating threat-related molecular programs that stimulate inflammation and contribute to increased risk of chronic illnesses., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Prior research demonstrates a protective role for oxytocin in ovarian cancer based on its anti-proliferative, anti-migratory, and anti-invasive effects in vitro and in vivo. However, the role of endogenous oxytocin has not been examined in ovarian cancer patients. Oxytocin also has anti-inflammatory properties that have not been examined in cancer. The purpose of this investigation was to examine relationships between endogenous oxytocin, tumor-associated inflammation (interleukin-6), and survival in advanced epithelial ovarian cancer patients., Methods: Tumor microenvironment (ascites) and plasma oxytocin levels were analyzed via ELISA on extracted samples obtained from 79 patients. In vitro models were used to characterize oxytocin and oxytocin receptor expression in four ovarian cancer cell lines and to investigate direct anti-inflammatory effects of oxytocin on tumor cell secretion of interleukin-6. High and variable levels of oxytocin were observed in ascites, up to 200 times greater than in plasma. Higher levels of ascites oxytocin were associated with lower levels of systemic and tumor-associated interleukin-6, an inflammatory cytokine implicated in ovarian tumor progression. Oxytocin also attenuated interleukin-6 secretion from multiple ovarian tumor cell lines in vitro. Higher levels of ascites oxytocin were associated with a significant survival advantage and statistical mediation analyses suggested this effect was partially mediated by interleukin-6., Conclusions: These data identify a previously unacknowledged hormone in the ovarian tumor microenvironment and provide initial evidence that oxytocin has protective effects in ovarian cancer via anti-inflammatory mechanisms. Future studies should examine the therapeutic utility of oxytocin., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Psychological stress and poor sleep are associated with a wide range of negative health outcomes, which are thought to be mediated in part by alterations in immune processes. However, the molecular bases of links among stress, sleep, and immune processes are not completely understood, particularly during adolescence when sensitivity to stress and problems with sleep tend to increase. In the current study, we investigated whether various stressors (daily stress, major life events, perceived stress), sleep indices (duration, efficiency), and their interactions (e.g., moderating effects) are associated with expression of genes bearing response elements for transcription factors that regulate inflammatory and anti-viral processes., Method: Eighty-seven late adolescents completed daily checklists of their social experiences across a 15-day period and reported on their major life events during the previous year. They also completed actigraphy-based assessments of sleep quality and duration during 8 consecutive nights. An average of 5.5 months later, participants reported on their global perceptions of stress during the previous month and provided blood samples for genome-wide expression profiling of mRNA from peripheral blood mononuclear cells (PBMCs)., Results: Higher levels of daily interpersonal stress and shorter sleep duration were associated with upregulation of inflammation-related genes bearing response elements for proinflammatory transcription factor nuclear factor kappa B (NF-κB). Shorter sleep duration was also linked to downregulation of antiviral-related genes bearing response elements for interferon response factors (IRFs). Lastly, there was a significant interaction between daily stress and shorter sleep duration, such that the association between daily stress and inflammation-related gene expression was exacerbated in the context of shorter sleep duration. Results were independent of sex, ethnicity, parent education, body mass index, and smoking and alcohol history., Conclusion: Everyday interpersonal stress and shortened sleep can be consequential for upstream NF-κB signaling pathways relevant to inflammatory processes during late adolescence. Notably, the occurrence of both may lead to even greater activation of NF-κB signaling., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The conserved transcriptional response to adversity (CTRA), characterized by increased expression of proinflammatory genes and decreased expression of antiviral and antibody-related genes, is upregulated in the context of chronic adversity and distress and has been linked to cancer progression. Several studies suggest that the CTRA may also be down-regulated in association with some positive psychological states, particularly eudaimonic well-being. However, it is not clear if the link between inter-individual differences in the CTRA and eudaimonic well-being can be extended to intra-individual change. Using a standardized mindfulness-based intervention, the current study tested whether mindfulness-related increases in eudaimonic well-being related to intra-individual reduction in the CTRA in a sample of younger breast cancer survivors., Methods: Participants were 22 women who had been diagnosed and treated for early-stage breast cancer at or before age 50 (M age  = 46.6 years) and had no evidence of active disease. Women completed self-report questionnaires and provided peripheral blood samples before and after a 6-week mindfulness meditation intervention. Regression analyses were used to quantify associations between the magnitude of change in eudaimonic well-being and the magnitude of change in the global CTRA score., Results: Women reported significant increases in eudaimonic well-being and showed decreased expression of the pro-inflammatory subcomponent of the CTRA from pre- to post-intervention. The magnitude of increase in eudaimonic well-being was associated with the magnitude of decrease in the composite CTRA score, and this relationship was driven primarily by increased expression of the antiviral/antibody-related CTRA subcomponent. While the intervention was also associated with reduced depressive symptoms, there was no association between change in depressive symptoms and change in the overall CTRA composite score or either of its subcomponents., Conclusions: Results are consistent with the hypothesis that eudaimonic well-being may be an important mechanism in interventions aimed at enhancing health in vulnerable groups, and contribute to our understanding of how psychological well-being may influence physical health in cancer patients., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Previous research has linked exposure to adverse social conditions with DNA damage and accelerated telomere shortening, raising the possibility that chronic stress may impact biological aging pathways, ultimately increasing risk for age-related diseases. Less clear, however, is whether these stress-related effects extend to additional hallmarks of biological aging, including cellular senescence, a stable state of cell cycle arrest. The present study aimed to investigate associations between psychosocial stress and two markers of cellular aging-leukocyte telomere length (LTL) and cellular senescence signal p16 INK4a . Seventy-three adults (M age  = 43.0, SD = 7.2; 55% female) with children between 8-13 years of age completed interview-based and questionnaire measures of their exposures to and experiences of stress, as well as daily reports of stress appraisals over an 8-week diary period. Blood samples were used to assess markers of cellular aging: LTL and gene expression of senescent cell signal p16 INK4a (CDKN2A). Random effects models covarying for age, sex, ethnicity/race, and BMI revealed that participants with greater chronic stress exposure over the previous 6 months (b = 0.011, p =  .04), perceived stress (b = 0.020, p <  .001), and accumulated daily stress appraisals over the 8-week period (b = 0.013, p =  .02) showed increased p16 INK4a . No significant associations with LTL were found. These findings extend previous work on the impact of stress on biological aging by linking chronic stress exposure and daily stressful experiences to an accumulation of senescent cells. Findings also support the hypothesis that chronic stress is associated with accelerated aging by inducing cellular senescence, a common correlate of age-related diseases., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Although falling in love is one of the most important and psychologically potent events in human life, the somatic implications of new romantic love remain poorly understood. Psychological, immunological, and reproductive perspectives offer competing predictions of the specific transcriptional regulatory shifts that might accompany the experience of falling in love. To characterize the impact of romantic love on human genome function, we conducted genome-wide transcriptome profiling of 115 circulating immune cell samples collected from 47 young women over the course of a 2-year longitudinal study. Analyses revealed a selective alteration in immune cell gene regulation characterized by up-regulation of Type I interferon response genes associated with CD1C+/BDCA-1+ dendritic cells (DCs) and CLEC4C+/BDCA-2+ DCs, and a reciprocal down-regulation of α-defensin-related transcripts associated with neutrophil granulocytes. These effects emerged above and beyond the effects of changes in illness, perceived social isolation, and sexual contact. These findings are consistent with a selective up-regulation of innate immune responses to viral infections (e.g., Type I interferons and DC) and with DC facilitation of sexual reproduction, and provide insight into the immunoregulatory correlates of one of the keystone experiences in human life., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Fatigue is a challenge in ovarian cancer survivorship and greatly impacts quality of life. In other cancer populations, fatigue has been associated with abnormal diurnal cortisol patterns. However, little is known about biological and behavioral factors in 5+-year ovarian cancer survivors and potential mechanisms underlying persistent fatigue have not been investigated in this population. Moreover, relationships between neuroendocrine and psychosocial factors in 5+-year ovarian cancer survivors have not been studied. We addressed these issues by examining relationships between diurnal cortisol rhythms, fatigue, life stress, and social support in 30 survivors of ovarian cancer who were assessed at least 5 years (mean=6.20years) following their primary diagnosis. Flatter diurnal cortisol slopes were associated with higher levels of fatigue, suggesting a role for HPA-axis dysregulation in sustained fatigue experienced by survivors. Moreover, greater cumulative lifetime stressor exposure (p=0.023) and stressor severity (p=0.004) were associated with flatter diurnal cortisol slopes, while higher social attachment (p=0.001) was associated with steeper diurnal cortisol slopes. These findings suggest that ovarian cancer survivors with greater lifetime stress exposure or lower social attachment may be at increased risk for circadian rhythm disruption, which in turn is associated with fatigue. Future research should examine relationships of clinical stage and inflammatory cytokines to cortisol rhythms and fatigue in long-term ovarian cancer survivors, as well as investigating the clinical significance of abnormal diurnal cortisol profiles in this population., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Context: Prosocial behavior is linked to longevity, but few studies have experimentally manipulated prosocial behavior to identify the causal mechanisms underlying this association. One possible mediating pathway involves changes in gene expression that may subsequently influence disease development or resistance., Design, Setting, Participants: In the current study, we examined changes in a leukocyte gene expression profile known as the Conserved Transcriptional Response to Adversity (CTRA) in 159 adults who were randomly assigned for 4 weeks to engage in prosocial behavior directed towards specific others, prosocial behavior directed towards the world in general, self-focused kindness, or a neutral control task., Results: Those randomized to prosocial behavior towards specific others demonstrated improvements (i.e., reductions) in leukocyte expression of CTRA indicator genes. No significant changes in CTRA gene expression were observed in the other 3 conditions., Conclusion: These findings suggest that prosocial behavior can causally impact leukocyte gene expression profiles in ways that might potentially help explain the previously observed health advantages associated with social ties., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Previous research has shown that adverse social conditions may promote a conserved transcriptional response to adversity (CTRA) involving up-regulation of proinflammatory gene expression and down-regulation of Type I interferon anti-viral genes in circulating blood cells. However, the impact of social conditions on lymphoid tissue gene regulation remains largely unexplored. This project assessed how social instability in adult male rhesus macaques (N=10, 5 in unstable, and 5 in stable social conditions) might regulate gene expression within secondary lymphoid tissue (lymph nodes; LN). Unstable social conditions down-regulated axillary LN expression of genes involved in Type I interferon anti-viral responses. Transcript origin analyses implicated monocytes and B cells as cellular mediators of these effects, and promoter-based bioinformatics analyses indicated reduced activity of AP-1, NF-κB, IRF, and CREB transcription factors within the axillary LN microenvironment. Although the current study is limited in sample size, these results suggest that social influences on immune cell gene regulation extend beyond the circulating leukocyte pool to alter generalized transcriptome profiles in secondary lymphoid tissue, and they do so in a regulatory program that resembles the pattern of antiviral inhibition previously observed in circulating leukocytes., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: Cognitive behavioral stress management (CBSM) is an empirically-validated group-based psychosocial intervention. CBSM is related to decreased self-reported indicators of psychological adversity during breast cancer treatment and greater disease-free survival (DFS) vs. a control condition. This study examined relationships between CBSM, DFS, and a potential biobehavioral pathway linking these variables in breast cancer patients through a gene expression composite representing the leukocyte conserved transcriptional response to adversity (CTRA)., Design: Women with stage 0-IIIb breast cancer completed questionnaires and provided blood samples post-surgery. Participants were randomized to 10-week group-based CBSM or a psychoeducation control group and followed at 6 months, 12 months, and median 11 years. In total, 51 participants provided blood data for longitudinal analyses (CBSM n=28; Control n=23). Mixed model analyses examined CBSM effects on 6-12 month changes in CTRA expression (53 indicator genes representing pro-inflammatory, anti-viral and antibody production signaling). Cox regression models assessed the relationship between 6 and 12 month changes in CTRA expression and 11-year DFS., Results: Patients randomized to CBSM showed attenuated 6-12 month change in CTRA gene expression, whereas patients randomized to control showed increased CTRA expression (p=0.014). Average DFS was 5.92 years (SD=3.90). Greater 6-12 month CTRA increases predicted shorter 11-year DFS controlling for covariates (p=0.007)., Conclusions: CBSM attenuated CTRA gene expression during the initial year of breast cancer treatment. In turn, greater increases in CTRA gene expression predicted shorter long-term DFS. These findings identify a biobehavioral oncology pathway to examine in future work., Competing Interests: Dr. Antoni reports receiving publication royalties from a book he co-authored on cognitive-behavioral stress management., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The meaning in life, typically reflected in a sense of purpose, growth, or social embeddedness (called eudaimonic well-being, EWB), has been linked to favorable health outcomes. In particular, this experience is inversely associated with the conserved transcriptional response to adversity (CTRA), which involves up-regulation of genes linked to inflammation and down-regulation of genes linked to viral resistance. So far, however, little is known about how this transcriptome profile might be situated in specific socio-cultural contexts. Here, we tested 106 male workers at a large Japanese IT firm and found that the CTRA is inversely associated not only with general EWB but also with a more contextualized sense of meaning derived from the perceived significance of one's work and a sense of interdependence with others in the workplace. These results expand previous links between personal well-being and CTRA gene expression to include the socio-cultural determinants of meaning in life., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Chronic social adversity activates a conserved transcriptional response to adversity (CTRA) marked by increased expression of pro-inflammatory genes and decreased expression of antiviral- and antibody-related genes. Recent findings suggest that some psychological resilience factors may help buffer CTRA activation, but the relative impact of resilience and adversity factors remains poorly understood. Here we examined the relative strength of CTRA association for the two best-established psychological correlates of CTRA gene expression-the risk factor of perceived social isolation (loneliness) and the resilience factor of eudaimonic well-being (purpose and meaning in life)., Methods: Peripheral blood samples and validated measures of loneliness and eudaimonic well-being were analyzed in 108 community-dwelling older adults participating in the longitudinal US Health and Retirement Study (56% female, mean age 73). Mixed effect linear model analyses quantified the strength of association between CTRA gene expression and measures of loneliness and eudaimonic well-being in separate and joint analyses., Results: As in previous studies, separate analyses found CTRA gene expression to be up-regulated in association with loneliness and down-regulated in association with eudaimonic well-being. In joint analyses, effects of loneliness were completely abrogated whereas eudaimonic well-being continued to associate with CTRA down-regulation. Similar eudaimonia-dominant effects were observed for positive and negative affect, optimism and pessimism, and anxiety symptoms. All results were independent of demographic and behavioral health risk factors., Conclusions: Eudaimonic well-being may have the potential to compensate for the adverse impact of loneliness on CTRA gene expression. Findings suggest a novel approach to targeting the health risks associated with social isolation by promoting purpose and meaning in life., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Unlabelled: One proposed mechanism for the association between social isolation and poor health outcomes is inflammation. Lonely or socially disconnected individuals show greater inflammatory responses, including up-regulation of pro-inflammatory gene expression, and people who are sensitive to cues of social disconnection (e.g., high levels of anxious attachment) exhibit greater inflammation in response to psychological stress. However, no studies have examined how sensitivity to social disconnection may influence pro-inflammatory responses to an inflammatory challenge. In the present study, we investigated the impact of sensitivity to social disconnection (a composite score comprised of loneliness, anxious attachment, fear of negative evaluation, and rejection sensitivity) on pro-inflammatory cytokines and gene expression in response to endotoxin, an inflammatory challenge, vs. placebo in a sample of one hundred and fifteen (n=115) healthy participants. Results showed that those who are more sensitive to social disconnection show increased pro-inflammatory responses (i.e., increased levels of tumor necrosis factor-alpha and interleukin-6) to endotoxin, as well as up-regulation of multiple genes related to inflammation. Furthermore, bioinformatics analyses revealed that those in the endotoxin group who are more sensitive to social disconnection exhibited a conserved transcriptional response to adversity (CTRA) regulatory profile, involving up-regulation of beta-adrenergic and pro-inflammatory transcription control pathways and down-regulation of antiviral transcription factors in response to endotoxin. These results may ultimately have implications for understanding the links between social isolation, inflammation, and health., Clinical Trials Registration: ClinicalTrials.gov NCT01671150., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Introduction: Hypothalamic-pituitary-adrenal (HPA) deregulation is commonly observed in cancer patients, but its clinical significance is not well understood. We prospectively examined the association between HPA activity, tumor-associated inflammation, and survival in ovarian cancer patients prior to treatment., Materials and Methods: Participants were 113 women with ovarian cancer who provided salivary cortisol for three days prior to treatment for calculation of cortisol slope, variability, and night cortisol. Cox proportional hazard regression analyses were used to examine associations between cortisol and survival in models adjusting for disease stage, tumor grade, cytoreduction and age. On a subsample of 41 patients with advanced disease ascites fluid was assayed for levels of interleukin-6 (IL-6) and correlated with cortisol variables., Results: Each cortisol measure was associated with decreased survival time, adjusting for covariates (all p<.041). A one standard deviation increase in night cortisol was associated with a 46% greater likelihood of death. Patients in the high night cortisol group survived an estimated average of 3.3 years compared to 7.3 years for those in the low night cortisol group. Elevated ascites IL-6 was associated with each cortisol measure (all r>36, all p<.017)., Discussion: Abnormal cortisol rhythms assessed prior to treatment are associated with decreased survival in ovarian cancer and increased inflammation in the vicinity of the tumor. HPA abnormalities may reflect poor endogenous control of inflammation, dysregulation caused by tumor-associated inflammation, broad circadian disruption, or some combination of these factors. Nocturnal cortisol may have utility as a non-invasive measure of HPA function and/or disease severity., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The temporal and situational stability of personality has led generations of researchers to hypothesize that personality may have enduring effects on health, but the biological mechanisms of such relationships remain poorly understood. In the present study, we utilized a functional genomics approach to examine the relationship between the 5 major dimensions of personality and patterns of gene expression as predicted by 'behavioural immune response' theory. We specifically focussed on two sets of genes previously linked to stress, threat, and adverse socio-environmental conditions: pro-inflammatory genes and genes involved in Type I interferon and antibody responses., Methods: An opportunity sample of 121 healthy individuals was recruited (86 females; mean age 24 years). Individuals completed a validated measure of personality; questions relating to current health behaviours; and provided a 5ml sample of peripheral blood for gene expression analysis., Results: Extraversion was associated with increased expression of pro-inflammatory genes and Conscientiousness was associated with reduced expression of pro-inflammatory genes. Both associations were independent of health behaviours, negative affect, and leukocyte subset distributions. Antiviral and antibody-related gene expression was not associated with any personality dimension., Conclusions: The present data shed new light on the long-observed epidemiological associations between personality, physical health, and human longevity. Further research is required to elucidate the biological mechanisms underlying these associations., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Experimental studies in preclinical mouse models of breast cancer have shown that chronic restraint stress can enhance disease progression by increasing catecholamine levels and subsequent signaling of β-adrenergic receptors. Catecholamines also signal α-adrenergic receptors, and greater α-adrenergic signaling has been shown to promote breast cancer in vitro and in vivo. However, antagonism of α-adrenergic receptors can result in elevated catecholamine levels, which may increase β-adrenergic signaling, because pre-synaptic α2-adrenergic receptors mediate an autoinhibition of sympathetic transmission. Given these findings, we examined the effect of α-adrenergic blockade on breast cancer progression under non-stress and stress conditions (chronic restraint) in an orthotopic mouse model with MDA-MB-231HM cells. Chronic restraint increased primary tumor growth and metastasis to distant tissues as expected, and non-selective α-adrenergic blockade by phentolamine significantly inhibited those effects. However, under non-stress conditions, phentolamine increased primary tumor size and distant metastasis. Sympatho-neural gene expression for catecholamine biosynthesis enzymes was elevated by phentolamine under non-stress conditions, and the non-selective β-blocker propranolol inhibited the effect of phentolamine on breast cancer progression. Selective α2-adrenergic blockade by efaroxan also increased primary tumor size and distant metastasis under non-stress conditions, but selective α1-adrenergic blockade by prazosin did not. These results are consistent with the hypothesis that α2-adrenergic signaling can act through an autoreceptor mechanism to inhibit sympathetic catecholamine release and, thus, modulate established effects of β-adrenergic signaling on tumor progression-relevant biology., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Yoga is a popular mind-body therapy that has demonstrated beneficial effects on psychological, behavioral, and functional outcomes. However, few studies have investigated effects on inflammatory processes. This study tested the hypothesis that an Iyengar yoga intervention specifically designed for fatigued breast cancer survivors would lead to decreases in inflammation-related gene expression and circulating markers of proinflammatory cytokine activity., Methods: Breast cancer survivors with persistent cancer-related fatigue were randomized to a 12-week Iyengar yoga intervention (n=16) or a 12-week health education control condition (n=15). Blood samples were collected at baseline, post-intervention, and at a 3-month follow-up for genome-wide transcriptional profiling and bioinformatic analyses. Plasma inflammatory markers and salivary cortisol were also assessed., Results: In promoter-based bioinformatics analyses, the yoga group showed reduced activity of the pro-inflammatory transcription factor nuclear factor kappa B (NF-κB), increased activity of the anti-inflammatory glucocorticoid receptor, and reduced activity of cAMP response element-binding protein (CREB) family transcription factors relative to controls (all ps<.05). There was also a significant intervention effect on the soluble tumor necrosis factor receptor type II (sTNF-RII), a marker of TNF activity; plasma levels of sTNF-RII remained stable in the yoga group, whereas levels of this marker increased in the health education group (p=.028). A similar, non-significant trend was observed for the interleukin 1 receptor antagonist (p=.16). No significant changes in C reactive protein (CRP), interleukin 6 (IL-6), or diurnal cortisol measures were observed., Conclusions: A 12-week restorative Iyengar yoga intervention reduced inflammation-related gene expression in breast cancer survivors with persistent fatigue. These findings suggest that a targeted yoga program may have beneficial effects on inflammatory activity in this patient population, with potential relevance for behavioral and physical health., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Although yoga and meditation have been used for stress reduction with reported improvement in inflammation, little is known about the biological mechanisms mediating such effects. The present study examined if a yogic meditation might alter the activity of inflammatory and antiviral transcription control pathways that shape immune cell gene expression., Methods: Forty-five family dementia caregivers were randomized to either Kirtan Kriya Meditation (KKM) or Relaxing Music (RM) listening for 12 min daily for 8 weeks and 39 caregivers completed the study. Genome-wide transcriptional profiles were collected from peripheral blood leukocytes sampled at baseline and 8-week follow-up. Promoter-based bioinformatics analyses tested the hypothesis that observed transcriptional alterations were structured by reduced activity of the pro-inflammatory nuclear factor (NF)-κB family of transcription factors and increased activity of Interferon Response Factors (IRFs; i.e., reversal of patterns previously linked to stress)., Results: In response to KKM treatment, 68 genes were found to be differentially expressed (19 up-regulated, 49 down-regulated) after adjusting for potentially confounded differences in sex, illness burden, and BMI. Up-regulated genes included immunoglobulin-related transcripts. Down-regulated transcripts included pro-inflammatory cytokines and activation-related immediate-early genes. Transcript origin analyses identified plasmacytoid dendritic cells and B lymphocytes as the primary cellular context of these transcriptional alterations (both p<.001). Promoter-based bioinformatic analysis implicated reduced NF-κB signaling and increased activity of IRF1 in structuring those effects (both p<.05)., Conclusion: A brief daily yogic meditation intervention may reverse the pattern of increased NF-κB-related transcription of pro-inflammatory cytokines and decreased IRF1-related transcription of innate antiviral response genes previously observed in healthy individuals confronting a significant life stressor., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Functional genomics strategies have been slow to penetrate research on human stress and coping, but recent conceptual advances have yielded a raft of new findings relating social and psychological conditions to broad alterations in human gene expression. This article reviews the field of human stress genomics, analyzes some of the conceptual and technical issues that initially hampered its progress, and outlines an abstractionist approach to genomic data analysis that has revealed a surprisingly consistent pattern of human transcriptional responses to diverse types of socio-environmental adversity. This field is now poised for another round of significant advances as research begins to incorporate the effects of DNA polymorphism, target a broader array of healthy and diseased tissues, and identify general teleologic and regulatory themes by pooling results over a growing body of studies analyzing the human transcriptional response to stress., (Copyright 2010 Elsevier Ltd. All rights reserved.)